The invention herein is directed to an expansion of the use of selective inhibitors of cyclooxygenase-2 and of natural substances which inhibit cyclooxygenase-2.
Prostaglandins are important mediators of inflammation that are produced at elevated levels in inflamed tissues. The increased amounts of prostaglandins produced in inflamed tissues reflect enhanced synthesis, which occurs by cyclooxygenase-catalyzed metabolism of arachidonic acid. Two different isoforms of cyclooxygenase (COX) designated cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) have been identified. COX-1 is a constitutive isoform present in most tissues. COX-2 is not detectable in most normal tissues, but it is induced by cytokines, growth factors, oncogenes and tumor promoters. The increased production of prostaglandins in the joints of patients with rheumatoid arthritis has been attributed to elevated levels of COX-2.
Traditional nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin inhibit the activities of COX-1 and COX-2 and therefore the synthesis of pro-inflammatory prostaglandins. NSAID-mediated inhibition of COX-1 is believed to be responsible for side effects such as peptic ulcer disease. Selective inhibitors of COX-2 have been developed in an effort to decrease the side effects of traditional NSAIDs. In fact, selective inhibitors of COX-2 do appear to be very effective inhibitors of rheumatoid arthritis while causing fewer gastrointestinal side effects than traditional NSAIDs.
While aspirin has been used to treat sore throat, heretofore there has been no proof that COX-2 is upregulated in sore throat and no suggestion of the use of selective inhibitors of COX-2 or of use of COX-2 inhibitors from natural sources, to treat sore throat.
While nitric oxide synthase inhibitors have been suggested for treating acute and chronic inflammatory diseases including sinusitis (see Williamson et al. U.S. Pat. No. 5,710,181), heretofore there has been no description of the use of selective inhibitors of COX-2 or of the use of COX-2 inhibitors from natural sources, to treat sinusitis.
The invention herein is directed to a method for treating a patient with an inflammatory disease of the head and neck comprising administering to said patient a therapeutic amount of a selective inhibitor of cyclooxygenase-2 or of a cyclooxygenase-2 inhibitor from a natural source.
The term xe2x80x9cinflammatory disease of the head and neckxe2x80x9d includes, without limitation, sore throat, e.g., that caused by tonsillitis or pharyngitis, and sinusitis.
The term xe2x80x9ctonsillitisxe2x80x9d is used herein to mean an acute inflammation of the palatine tonsils and includes tonsillitis caused by bacterial and viral infections.
The term xe2x80x9cpharyngitisxe2x80x9d is used herein to mean an acute inflammation of the pharynx and includes pharyngitis caused by bacterial and viral infections.
The term xe2x80x9csinusitisxe2x80x9d is used herein to mean an inflammatory process in the paranasal sinuses and includes such condition caused by viral, bacterial and fungal infections or allergic reactions.
The term xe2x80x9cinhibitor of cyclooxygenase-2xe2x80x9d is used herein to mean a compound which directly inhibits cyclooxygenase-2 metabolized catalysis of arachidonic acid and/or inhibits the transcription of cyclooxygenase-2 and excludes nitric oxide synthase inhibitors. The term includes competitive inhibitors as well as non-competitive inhibitors.
The term xe2x80x9cselective inhibitor of cyclooxygenase-2xe2x80x9d is used herein to mean compound which selectively inhibits cyclooxygenase-2 in preference to cyclooxygenase-1 and particularly compound for which the ratio of the IC50 concentration (concentration inhibiting 50% of activity) for cyclooxygenase-1 to the IC50 concentration for cyclooxygenase-2 is greater than 1. Such ratio is readily determined by assaying for cyclooxygenase-2 activity and assaying for cyclooxygenase-1 activity by the methods set forth at column 39, line 55xe2x80x94column 40, line 36 of Talley et al. U.S. Pat. No. 5,633,272, which is incorporated herein by reference, and from the resulting data obtaining a ratio of IC50s.
The term xe2x80x9cnatural sourcexe2x80x9d in the phrase xe2x80x9ccyclooxygenase-2 inhibitor from a natural sourcexe2x80x9d is a plant, marine or animal organism.
We turn firstly to the selective inhibitors of cyclooxygenase-2. The selective inhibitors of cyclooxygenase-2 are synthetic compounds.
The selective inhibitors of cyclooxygenase-2 are preferably those where the ratio of the IC50 concentration for cyclooxygenase-1 to the IC50 concentration for cyclooxygenase-2 is 100 or more.
Selective inhibitors of cyclooxygenase-2 include the following compounds:
(1) 4-[5-(4-Chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide
(2) 4-[5-(4-Bromophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide
(3) 4-[5-(3-Chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide
(4) 4-[5-(4-Methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide
(5) 4-[5-(2-Chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide
(6) 4-[5-(4-Trifluoromethylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide
(7) 4-[5-(4-Fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide
(8) 4-[5-Phenyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide
(9) 4-[5-(4-Methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide
(10) 4-[5-(4-Trifluoromethoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide
(11) 4-[5-(2-Methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide
(12) 4-[5-(4-Chlorophenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide
(13) 4-[4-(Aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazol-3-carboxylate
(14) 4-[4-(Aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazol-3-carboxamide
(15) 4-[5-(4-[Methylthio]phenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide
(16) 4-[5-(4-[Methylsulfonyl]phenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide
(17) 4-[5-(2,4-[Difluoro]phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide
(18) 4-[5-(2,6-[Difluoro]phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide
(19) 4-[5-(4-Cyanophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide
(20) 4-[5-(4-Chlorophenyl)-3-(heptafluoropropyl)-1H-pyrazol-1-yl]benzenesulfonamide
(21) 4-[5-(4-Chlorophenyl)-3-(chloro-difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide
(22) 4-[5-(4-Chlorophenyl)-3-(pentafluoroethyl)-1H-pyrazol-1-yl]benzenesulfonamide
(23) 4-[5-(4-Biphenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide
(24) 4-[5-(4-Pyrazinyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide
(25) 4-[5-(5-Chloro-2-thienyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide
(26) 4-[5-(4-Morpholino)phenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide
(27) 4-[5-(1-Cyclohexyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide
(28) 4-[5-(5-Bromo-2-thienyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide
(29) 4-[5-(4-Thienyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide
(30) 4-[5-(4-[Trifluoromethyl]phenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide
(31) 4-[5-(3,4-Dichlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide
(32) 4-[5-(2,4-Dichlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide
(33) 4-[5-Phenyl-3-(3-hydroxypropyl)-1H-pyrazol-1-yl]benzenesulfonamide
(34) 4-[5-(4-Fluorophenyl)-3-(3-hydroxypropyl)-1H-pyrazol-1-yl]benzenesulfonamide
(35) 4-[4-(Aminosulfonyl)phenyl]-5-(4-fluorophenyl)-1H-pyrazole]-3-propanoic acid
(36) 4,5-Dihydro-4-[3-trifluoromethyl]-1H-benz[g]indazol-1-yl]benzenesulfonamide
(37) 4-[5-(4-Chlorophenyl)-4-chloro-1H-pyrazol-1-yl]benzenesulfonamide
(38) 4-[5-(4-Chlorophenyl)-3-(trifluoromethyl)-4-chloro-1H-pyrazol-1-yl]benzenesulfonamide
(39) 4-[1-(4-Fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]benzenesulfonamide
(40) 1-(2,4,6-Trichlorobenzoyl)-5-methoxy-2-methyl-3-indolyl acetic acid
(41) 1-(2,6-dichlorobenzoyl)-5-methoxy-2-methyl-3-indolyl acetic acid
(42) 3-(4-Aminosulfonyl)phenyl)-2-(4-fluorophenyl)-5-(2-hydroxy-2-propyl)thiophene
(43) 3-(4-(Aminosulfonyl)phenyl-2-(4-fluorophenyl-thiophene
(44) 3-(4-(Aminosulfonyl)phenyl)-2-(4-fluorophenyl)-5-(2-propyl)thiophene
(45) 3-(4-(Aminosulfonyl)phenyl)-2-cyclohexylthiophene
(46) 5-(4-Carboxyphenyl)-4-(4-(methylsulfonyl)phenyl)thiophene-2-carboxylic acid
(47) 4-(4-Fluorophenyl)-2-methyl-5-(4-(methylsulfonyl)phenyl)thiazole
(48) 2-(4-Fluorophenyl)-3-(4-methylsulfonyl)phenyl)-2-cyclopenten-1-one
(49) 4-(4-(Methylsulfonyl)phenyl-5-(4-fluorophenyl)-isothiazole
(50) 3-(4-Fluorophenyl)-4-(4-(methylsulfonyl)phenyl-2-(5H)-furanone
(51) 3-(4-Fluorophenyl)-4-(4-(aminosulfonyl)phenyl)-2-(2H)-furanone
(52) 3-(4-Fluorophenyl)-4-(4-(methylsulfonyl)phenyl)furan
(53) 5,5-Dimethyl-3-(4-fluorophenyl)-4-(4-methylsulfonyl-phenyl)-2-(5H)furanone
(54) 2-((4-Aminosulfonyl)phenyl)-3-(4-fluorophenyl)thiophene
(55) 3-(2,4-Difluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone
(56) 3-(3,4-Difluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone
(57) 3-(2,6-Difluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone
(58) 3-(2,5-Difluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone
(59) 3-(3,5-Difluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone
(60) 3-(4-Bromophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone
(61) 3-(4-Chlorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone
(62) 3-(4-Methoxyphenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone
(63) 3-(Phenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone
(64) 3-(2-Chlorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone
(65) 3-(2-Bromo-4-fluorophenyl)-4-(4-(methylsulfon-yl)phenyl)-2-(5H)-furanone
(66) 3-(2-Bromo-4-Chlorophenyl)-4-(4-(methylsulfon-yl)phenyl)-2-(5H)-furanone
(67) 3-(4-Chloro-2-fluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone
(68) 3-(3-Bromo-4-fluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone
(69) 3-(3-Chlorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone
(70) 3-(2-Chloro-4-fluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone
(71) 3-(2,4-Dichlorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone
(72) 3-(3,4-Dichlorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone
(73) 3-(2,6-Dichlorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone
(74) 3-(3-Chloro-4-fluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone
(75) 3-(4-Trifluoromethylphenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone
(76) 3-(3-Fluoro-4-methoxyphenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone
(77) 3-(3-Chloro-4-methoxyphenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone
(78) 3-(3-Bromo-4-methoxyphenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone
(79) 3-(2-Fluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone
(80) 3-(4-Methylthiophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone
(81) 3-(3-Fluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone
(82) 3-(2-Chloro-6-fluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone
(83) 3-(3-Bromo-4-methylphenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone
(84) 3-(4-Bromo-2-fluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone
(85) 3-(3,4-Dibromophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone
(86) 3-(4-Chloro-3-fluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone
(87) 3-(4-Bromo-3-fluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone
(88) 3-(4-Bromo-2-chlorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone
(89) 3-(2-Naphthyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone
(90) 3-(7-Quinolinyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone
(91) 3-(3,4-Dichlorophenyl)-4-(4-(aminosulfonyl)phenyl)-2-(2H)-furanone
(92) 3-(3,4-Dichlorophenyl)-4-(4-(aminosulfonyl)phenyl)-2-(2H)-furanone
(93) 3-(3,4-Dichlorophenyl)-4-(4-(aminosulfonyl)phenyl)-2-(2H)-furanone
(94) 3-(3-Bromo-4-methoxyphenyl)-4-(4-(aminosulfonyl)phenyl)-2-(2H)-furanone
(95) 3-(4-(Methylsulfonyl)phenyl)-2-phenylbenzo[b]furan
(96) 3-(4-Methylsulfonyl)phenyl)-2-phenylbenzo[b]thiophene
(97) 3-(4-Methylsulfonyl)phenyl-2-phenylinden-1-one
(98) 2-(4-Fluorophenyl)-3-(4-(methylsulfonyl)phenyl)indole
(99) 3-(4-Fluorophenyl)-2-(4-(methylsulfonyl)phenyl)indole
(100) 2-(4-Fluorophenyl)-3-(4-(methylsulfonyl)phenyl)-4H-thieno[2,3-c]-furan-6-one
(101) 2-(3,4-Difluorophenyl)-3-(4-(methylsulfonyl)phenyl)-4H-thieno[2,3-c]-furan-6-one
(102) 2-(4-Fluorophenyl)-3-(4-(aminosulfonyl)phenyl)-4H-thieno[2,3-c]-furan-6-one
(103) 2-(3,4-Difluorophenyl)-3-(4-(aminsulfonyl)phenyl)-4H-thieno[2,3-c]-furan-6-one
(104) 3-(4-(Methylsulfonyl)phenyl)-2-phenyl)-4,7-dihydro-thieno[2,3-c]pyran-5-one
(105) 2-(4-(Methylsulfonyl)phenyl)-3-phenyl)-4H-thieno[2,3-c]furan-6-one
(106) 5-(4-(Methylsulfonyl)phenyl)-6-phenylimidazo[2,1-b]thiazole
(107) 2-Methyl-5-(4-(methylsulfonyl)phenyl)-6-phenylimidazo[2,1-b]thiazole
(108) 3-Methyl-5-(4-(methylsulfonyl)phenyl)-6-phenylimidazo[2,1-b]thiazole
(109) 2-Bromo-5-(4-(methylsulfonyl)phenyl)-6-phenylimidazo[2,1-b]thiazole
(110) 3-Trifluoromethyl-5-(4-(methylsulfonyl)phenyl)-6-phenylimidazo[2,1-b]thiazole
(111) 2,3-Dimethyl-5-(4-(methylsulfonyl)phenyl)-6-phenyl-imidazo[2,1-b]thiazole
(112) 5-(4-(Methylsulfonyl)phenyl)-6-(4-fluorophenyl)imidazo[2,1-b]thiazole
(113) 5-Phenyl)-6-(4-(methylsulfonyl)phenyl)-imidazo[2,1-b]thiazole
(114) 2-Chloro-5-(4-(methylsulfonyl)phenyl)-6-(4-chlorophenyl)imidazo[2,1-b]thiazole
(115) 2,2-Dichloro-5-(4-(methylsulfonyl)phenyl)-6-(4-chlorophenyl)imidazo[2,1-b]thiazole
(116) 5-(4-(Methylsulfonyl)phenyl)-6-(imidazo[2,1-b]-1,3,4-thiadiazole
(117) 5-Phenyl-6-(4-(methylsulfonyl)phenyl)-imidazo[2,1-b]-1,3,4-thiadiazole
(118) 2-Methyl-5-(4-(methylsulfonyl)phenyl)-6-phenyl-imidazo[2,1-b]-1,3,4-thiadiazole
(119) 2-Methyl-5-phenyl-6-(4-methylsulfonyl)phenyl)-imidazo[2,1-b]-1,3,4-thiadiazole
(120) 5-(4-(Methylsulfonyl)phenyl)-6-(4-fluorophenyl)-imidazo[2,1-b]-1,3,4-thiadiazole
(121) 5-(4-(Methylsulfonyl)phenyl)-6-phenyl-1H-imidazo[2,1-b]-s-thiazole
(122) 5-Phenyl-6-(4-(methylsulfonyl)phenyl)thiazolo[3,2-b]-1,3,4-triazole
(123) 2,3-Dihydro-5-(4-(methylsulfonyl)phenyl)-6-phenylimidazo[2,1-b]thiazole
(124) 2-[(4-Methylthio)phenyl]-1-biphenyl
(125) 1-Cyclohexene-2-(4xe2x80x2-methylsulfonylphenyl)benzene
(126) 3-(4xe2x80x2-Methylsulfonylphenyl)-4-phenylphenol
(127) 1-[2-(4-Methylsulfonylphenyl)phenyl]piperidine
(128) 1-[2-(4xe2x80x2-Methylsulfonylphenyl)phenyl]pyrrole
(129) 1-Phenoxy-2-(4xe2x80x2-methylsulfonylphenyl)benzene
(130) 5-(4-Fluorophenyl)-2-methoxy-4-[4-(methylsulfon-yl)phenyl]-6-(trifluoromethyl)pyridine
(131) 2-Ethoxy-5-(4-fluorophenyl)-4-[4-(methylsulfon-yl)phenyl]-6-(trifluoromethyl)pyridine
(132) 5-(4-Fluorophenyl)-4-[4-(methylsulfonyl)phenyl]-2-(2-propynyloxy)-6-(trifluoromethyl)pyridine
(133) 2-Bromo-5-(4-fluorophenyl)-4-[4-(methylsulfon-yl)phenyl]-6-(trifluoromethyl)pyridine
(134) 3-[1-(p-Bromobenzyl)-5-methoxy-2-methylindol-3-yl]propanoic acid
(135) 3-[1-(p-Bromobenzyl)-5-methoxy-2-methylindol-3-yl]butanoic acid, sodium salt
(136) 2-Benzyl-3-[1-(p-bromobenzyl)-5-methoxy-2-methylindol-3-yl-propanoic acid
(137) 3-[1-(p-Bromobenzyl)-5-methoxy-2-methylindol-3-yl]-2,2-dimethylpropanoic acid
(138) 3-[1-(p-Bromobenzyl)-5-methoxy-2-methylindol-3-yl]-4,4,4-trifluorobutanoic acid, sodium salt
(139) trans-2-[1-(p-Bromobenzyl)-5-methoxy-2-methylindol-3-yl]-cyclo-propanecarboxylic acid, sodium salt
(140) 3-[1-(p-Bromobenzyl)-5-methoxy-2-methylindol-3-yl]-hydroxy-2-methyl propanoic acid, sodium salt
(141) [1(1-(p-Bromobenzyl)-5-methoxy-2-methylindol-3-yl]-cyclopropylacetic acid, sodium salt
(142) trans-(+)-2-[1-(p-Bromobenzyl)-5-methoxy-2-methylindol-3-yl]cyclopropanecarboxylic acid, sodium salt
(143) 3-[1-(p-Bromobenzyl)-5-methoxy-2-methylindol-3-yl]-2-methylpropanoic acid and sodium salt
(144) 3-[1-(p-Chlorobenzyl)-5-methoxy-2-methylindol-3-yl]-4,4,4-trifluorobutanoic acid and sodium salt
(145) syn-3-[1-(p-Bromobenzyl)-5-methoxy-2-methylindol-3-yl]-2-methylbutanoic acid
(146) anti-3-[1-(p-Bromobenzyl)-5-methoxy-2-methylindol-3-yl]-2-methylbutanoic acid and sodium salt
(147) 3-[5-(Bromo-1-(p-bromobenzyl)-2-methylindol-3-yl]butanoic acid and sodium salt
(148) (xe2x88x92)-3-[1-(p-Bromobenzyl)-5-methoxy-2-methylindol-3-yl]-butanoic acid and sodium salt
(149) (+)-3-[1-(p-Bromobenzyl)-5-methoxy-2-methylindol-3-yl]-butanoic acid and sodium salt
(150) trans-(xe2x88x92)-2-[1-(p-Bromobenzyl)-5-methoxy-2-methylindol-3-yl]cyclopropanecarboxylic acid and sodium salt
(151) 3-[1-(p-Bromobenzyl)-2,5-dimethylindol-3-yl]propanoic acid
(152) 3-[5-(Bromo-1-(p-bromobenzyl)-2-methylindol-3-yl]propanoic acid
(153) 3-[1-(p-Bromobenzyl)-5-chloro-2-methylindol-3-yl)propanoic acid
(154) 3-[1-(p-Chlorobenzyl)-5-methoxy-2-methylindol-3-yl)-2-methylpropanoic acid
(155) Methyl 3-[1-(p-bromobenzyl)-5-methoxy-2-methylindol-3-yl)propanoate
(156) 3-[1-(p-Bromobenzyl)-5-methoxy-2-methylindol-3-yl)-3-methylbutanoic acid
(157) 5-Methanesulfonamido-6-(2,4-difluorophenylthio)-1-indanone
(158) 5-Methanesulfonamido-6-(2,4-dichlorophenoxy)-1-indanone
(159) 2-(4-Chlorophenyl)-4-hydroxy-1-[4-(methylsulfo-nyl)phenyl]-4-(trifluoromethyl)-4,5-dihydro-1H-imidazole
(160) 2-(4-Chlorophenyl)-1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-1H-imidazole
(161) 1-(4-Fluorophenyl)-4-hydroxy-2-[4-(methylsulfo-nyl)phenyl]-4-(trifluoromethyl)-4,5-dihydro-1H-imidazole
(162) 1-(4-Fluorophenyl)-2-[4(methylsulfonyl)phenyl]-4-(trifluoromethyl)-1H-imidazole
(163) 2-(4-Chlorophenyl)-1-[4-methylsulfonyl)phenyl]-4-methyl-1H-imidazole
(164) 2-(4-Chlorophenyl)-1-[4-methylsulfonyl)phenyl]-4-phenyl-1H-imidazole
(165) 2-(4-Chlorophenyl)-4-(4-fluorophenyl)-1-[4-(methylsulfonyl)phenyl]-1H-imidazole
(166) 4-(4-Bromophenyl)-2-(4-chlorophenyl)-1-[4-(methylsulfo-nyl)phenyl]-1H-imidazole
(167) 2-(4-Chlorophenyl)-1-[4-(methylsulfonyl)phenyl]-4-(2-naphthyl)-1H-imidazole
(168) 2-(4-Chlorophenyl)-1-[4-(methylsulfonyl)phenyl]-4-[4-(trifluoromethoxy)phenyl]-1H-imidazole
(169) 2,4-Bis(4-chlorophenyl)-1-[4-(methylsulfonyl)phenyl]-1H-imidazole
(170) 2-(4-Chlorophenyl)-4-(3-chlorophenyl)-1-[4-(methylsulfonyl)phenyl]-1H-imidazole
(171) 2-(4-Chlorophenyl)-4-(4-methoxyphenyl)-1-[4-(methylsulfonyl)phenyl]-1H-imidazole
(172) 2-(4-Chlorophenyl)-4-(3-fluorophenyl)-1-[4-(methylsulfonyl)phenyl]-1H-imidazole
(173) 2-(4-Chlorophenyl)-4-[(4-chlorophenoxy)methyl]-1-[4-(methylsulfonyl)phenyl]-1H-imidazole
(174) 2-(3-Chloro-4-methylphenyl)-1-[4-(methylsulfo-nyl)phenyl]-4-(trifluoromethyl)-1H-imidazole
(175) 5-[1-[4-(Methylsulfonyl)phenyl)-4-(trifluoromethyl)-1H-imidazole-2-yl]-1,3-benzodioxole
(176) 2-(3-Fluoro-4-methoxyphenyl)-1-[4-(methylsulfonyl)-phenyl-4-(trifluoromethyl)-1H-imidazole
(177) 2-(4-Chlorophenyl)-4-[(phenylthio)methyl]-1-[4-(methylsulfonyl)phenyl]-1H-imidazole
(178) 2-(4-Chlorophenyl)-4-[(N-methyl-N-phenylamino)methyl]-1-[4-(methylsulfonyl)phenyl]-1H-imidazole
(179) 2-(4-Chlorophenyl)-4-[2-quinolyl)methoxymethyl]-1-[4-(methylsulfonyl)phenyl]-1H-imidazole
(180) 2-(4-Chlorophenyl)-4-methoxymethyl-1-[4-(methylsulfonyl)phenyl]-1H-imidazole
(181) 2-(4-Fluorophenyl)-1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1H-imidazole
(182) 1-[4-(Methylsulfonyl)phenyl]-2-phenyl-4-trifluoro-methyl-1H-imidazole
(183) 2-(3-Chloro-4-methoxyphenyl)-1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1H-imidazole
(184) 2-(4-Methylphenyl)-1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1H-imidazole
(185) 1-[4-(Methylsulfonyl)phenyl]-2-(4-trifluoromethyl-phenyl)-4-trifluomethyl-1H-imidazole
(186) 4-[2-(4-Chlorophenyl)-4-(trifluoromethyl)-1H-imidazol-1-yl]benzenesulfonamide
(187) 4-[2-(3-Chloro-4-methylphenyl)-4-(trifluoromethyl)-1H-imidazol-1-yl]benzenesulfonamide
(188) 3-[1-(4-Methylsulfonyl)phenyl]-4-trifluoromethyl-1H-imidazol-2-yl]pyridine
(189) 2-[1-(4-Methylsulfonyl)phenyl]-4-trifluoromethyl-1H-imidazol-2-yl]pyridine
(190) 4-[1-[4-(Methylsulfonyl)phenyl]-4-trifluoromethyl-1H-imidazol-2-yl]pyridine
(191) 2-Methyl-5-[1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1H-imidazol-2-yl]pyridine
(192) 2-Methyl-6-[1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1H-imidazol-2-yl]pyridine
(193) 5-Methyl-2-[1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1H-imidazol-2-yl]pyridine
(194) 4-Methyl-2-[1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1H-imidazol-2-yl]pyridine
(195) 2-Methoxy-5-[1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1H-imidazol-2-yl]pyridine
(196) 4-[2-(6-Methylpyridin-3-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl]benzenesulfonamide
(197) 4-[2-(6-Methylpyridin-2-yl)-4-(trifluoromethyl)-H-imidazol-1-yl]benzenesulfonamide
(198) 3-Methyl-5-[1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-1H-imidazol-2-yl]pyridine
(199) 4-[2-(4-Methylpyridin-2-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl]benzenesulfonamide
(200) 2-[1-[4-(Methylsulfonyl)phenyl]-4-(trifluoromethyl)-1H-imidazol-2-yl]thiophene
(201) 3-[1-[4-(Methylsulfonyl)phenyl]-4-(trifluoromethyl)-1H-imidazol-2-yl]thiophene
(202) 4-[2-(5-Methylpyridin-3-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl]benzenesulfonamide
(203) 2-Methyl-3-[1-[4-(methylsulfonyl)phenyl]-4-(trifluoro-methyl)-1H-imidazol-2-yl]thiophene
(204) 4-[2-(2-Methylpyridin-3-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl]benzenesulfonamide
(205) 4-[2-Pyridin-3-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl]benzenesulfonamide
The synthesis of compounds 1-39 is disclosed in Talley et al. U.S. Pat. No. 5,466,823. The synthesis of compounds 40 and 41 is disclosed in Black et al. U.S. Pat. No. 5,436,265. The synthesis of compounds 42-94 is disclosed in Ducharme et al. U.S. Pat. No. 5,474,995. The synthesis of compounds 95-105 is disclosed in Prasit et al. U.S. Pat. No. 5,521,213. The synthesis of compounds 106-123 is disclosed in Gauthier et al. U.S. Pat. No. 5,552,422. The synthesis of compounds 124-129 is disclosed in Batt U.S. Pat. No. 5,593,994. The synthesis of compounds 130-133 is disclosed in Lee U.S. Pat. No. 5,596,008. The synthesis of compounds 134-156 is disclosed in Lau et al. U.S. Pat. No. 5,604,253. The synthesis of compounds 157 and 158 is disclosed in Guay et al. U.S. Pat. No. 5,604,260. The synthesis of compounds 159-205 is disclosed in Khanna et al. U.S. Pat. No. 5,616,601.
Other selective inhibitors of cyclooxygenase-2 and their syntheses are taught in Examples 2-108, 110-129, 131-150, 152, 301-312, and 401-413 of Batt et al. U.S. Pat. No. 5,593,994, the disclosure of which is incorporated herein by reference. Still other selective inhibitors of cyclooxygenase-2 and their syntheses are taught in Examples 1-11, 13-16, and 18-25 of Guay et al. U.S. Pat. No. 5,604,260, the disclosure of which is incorporated herein by reference. Still other selective inhibitors of cyclooxygenase-2 and their syntheses are taught in Examples 1-13 including Examples 1a-1p and 4a-4h of Talley et al. U.S. Pat. No. 5,633,272, the disclosure of which is incorporated herein by reference. Still other selective inhibitors of cyclooxygenase-2 are taught in Examples 1-131 of Lau et al. U.S. Pat. No. 5,639,780, the disclosure of which is incorporated herein by reference. Still other selective inhibitors of cyclooxygenase-2 are taught in Examples 1-6 of Talley et al. U.S. Pat. No. 5,643,933, the disclosure of which is incorporated herein by reference. Still other selective inhibitors of cyclooxygenase-2 are taught in Examples 1-4 of Lau et al. U.S. Pat. No. 5,510,368, the disclosure of which is incorporated herein by reference.
Another example of a selective inhibitor of cyclooxygenase-2 useful herein are those which directly inhibit the enzyme cyclooxygenase-2 and which also inhibit the synthesis of cyclooxygenase-2 protein and which have antioxidant properties. These cyclooxygenase-2 inhibitors preferably contain phenyl group with two or more substituents selected from the group consisting of hydroxy and C1-4-alkoxy (e.g., methoxy) on the phenyl. Specific compounds of this class includes, for example, 4-[5-methyl-3-[[(2,3-hydroxy)phenoxy]methyl]-1H-pyrazol-1-yl]benzenesulfonamide and 4-methyl-5-(4-methylsulfonyl)phenyl-2-[(2,3-hydroxyphenoxy)methyl]oxazole and the corresponding compounds where methoxy or ethoxy replaces hydroxy. These compounds and their syntheses are described in Dannenberg Provisional Application No. 60/069,955 the entire disclosure of which is incorporated herein by reference.
A preferred selective inhibitor of cyclooxygenase-2 for use herein is 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide which is compound (4) set forth above. It is believed that this compound is celecoxib (Tradename Celebrex).
Another preferred selective inhibitor of cyclooxygenase is vioxx which is MK-0966; it is compound (63) set forth above.
The dosage of selective inhibitor of cyclooxygenase-2 for the method herein is a cyclooxygenase-2 inhibiting amount which is a therapeutically effective amount. In general, the dosage ranges from 0.1 to 30 mg/kg. The dosages for any particular agent will vary within said range. For compound (4) referred to above, the dosage preferably ranges from 3 to 12 mg/kg.
The route of administration of selective inhibitor of cyclooxygenase-2 is systemic or local for the treatment of sore throat including that caused by tonsillitis or pharyngitis. For systemic administration, the route of administration is preferably oral but other routes of systemic administration, e.g., parenteral such as intravenous, are also useful. For local administration, the selective inhibitor of cyclooxygenase-2 is applied directly to the sore tissue, e.g., formulated as a lozenge, oral rinse or spray.
The route of administration of selective inhibitor of cyclooxygenase-2 is systemic for the treatment sinusitis. Preferably, the route of administration is oral but other routes of systemic administration, e.g., parenteral such as intravenous, are also useful.
We turn now to the cyclooxygenase-2 inhibitors from natural sources. These cyclooxygenase-2 inhibitors from natural sources also inhibit cyclooxygenase-1.
The cyclooxygenase-2 inhibitors from natural sources include, for example, resveratrol, curcumin, caffeic acid phenethyl ester, ursolic acid, carnosol, shikonin and licochalcone A.
Resveratrol has the structure 
and is found in grapes and other foods. Inhibition by resveratrol of cyclooxygenase-2 transcription and activity is described in Subbaramaiah, K., et al., The Journal of Biological Chemistry, Vol. 273, 21875-21882 (1998).
The inventor herein has published abstracts showing that curcumin and caffeic acid phenethyl ester can inhibit cyclooxygenase-2.
The inhibitors of cyclooxygenase-2 from natural sources are preferably used as topical therapy for sore throats, e.g., tonsillitis and pharyngitis. In such case, the agent is readily administered as a lozenge, oral rinse or spray. In general, the dosages for inhibitors of cyclooxygenase-2 from natural sources used in this way ranges from 1 to 100 mg/kg. For resveratrol, a single application is, for example, 0.25 to 4 grams, administered from one to six times a day as needed.
The inhibitors of cyclooxygenase-2 from natural sources can be administered systemically for the treatment of sore throat or sinusitis. In such case, the route of administration is preferably oral but other routes of administration, e.g., parenteral such as intravenous, are also useful. In general, the dosage of inhibitors of cyclooxygenase-2 from natural sources for systemic administration ranges from 10 to 100 mg/kg and the dosage for resveratrol for systemic administration preferably ranges from 10 to 100 mg/kg.
The treatments are repeated from day-to-day as long as symptoms ameliorate. For tonsillitis, sore throat and pain are ameliorated. For pharyngitis, sore throat and pain on swallowing are ameliorated. For sinusitis, pain in the maxillary area and teeth and frontal headache are ameliorated.
One genus of inflammatory diseases herein constitutes diseases of the head and neck except for periodontitis.
In one embodiment herein, the inflammatory disease of the head and neck is periodontitis and the treating agent is a cyclooxygenase-2 inhibitor from a natural source. Thus, in this case, the method is for treating a patient with periodontitis and comprises administering to said patient a therapeutic amount of a cyclooxygenase-2 inhibitor from a natural source. The cyclooxygenase-2 inhibitors from a natural source are those described above and are preferably used as topical therapy for periodontitis. In such case, the agent is readily administered as a lozenge, oral rinse or spray. In such case, in general, the dosage ranges from 1 to 100 mg/kg. For resveratrol, a single application is, for example, 0.25 to 4 grams, administered one to six times a day. The cyclooxygenase-2 inhibitors from a natural source can also be administered systematically for the treatment of periodontitis. In such case, the route of administration is preferably oral but other routes of administration, e.g., parenteral such as intravenous are also useful. In general, the dosage for systemic administration ranges from 10 to 100 mg/kg, and the dosage for resveratrol for systemic administration preferably ranges from 10 to 100 mg/kg. The treatment is continued from day-to-day, as long as improvement occurs, e.g., as long as decrease in bleeding of gums and stopping of pocket formation and bone loss, occurs.